The treatment of diseases of the brain is significantly limited by the blood brain barrier (BBB) (Begley 1996; Begley 2004; Pardridge 2005; Deeken and Loscher 2007), wherein capillaries, characterised by an absence of fenestrae, are surrounded by astrocyte foot processes. Capillary endothelial cells are characterised by tight intercellular junctions, low pinocytotic activity and efflux transporters at their luminal surface. All of these features limit the passage of most molecules into the brain.
Prior brain targeting strategies have involved:
a) exploiting endogenous transporters for carrier mediated uptake (e.g. monoclonal antibody—drug conjugates or monoclonal antibody—particle conjugates) to exploit the human insulin or transferrin receptor (Pardridge 2007; Beduneau et al. 2008);
b) the inhibition of ABC transporters [e.g. P-glycoprotein (Bihorel et al. 2007) and breast cancer resistance protein (Deeken and Loscher 2007)];
c) the use of surfactant coated poly(butylcyanoacrylate) nanoparticles (Kreuter et al. 2003); and
d) the use of cationic carriers such as cationic albumin (Lu et al. 2006) and cationised forms of drug molecules (Girod et al. 1999).
All of these strategies use parenteral routes. However, preclinical mouse monoclonal antibody work has not translated into success in the clinic and the inhibition of high capacity ABC transporters, which are not exclusive to the BBB, is also not a viable clinical option.
Most peptide drugs are large in comparison to the vast majority of non-peptide drugs. They typically have molecular weights in excess of 500 Da, which means that diffusion across biological barriers is slow, resulting in poor oral absorption into the blood stream. They are usually hydrophilic and have a significant potential to form hydrogen bonds in aqueous environments. In addition, they often contain several ionisable groups and hence are typically charged at physiological pH. Peptides are also susceptible to degradation within the gastrointestinal tract by carboxy peptidases and amino peptidases. When taken in combination, these factors mean that unmodified peptides are typically very poor candidates for oral delivery, based upon structure alone. Furthermore peptides, even if absorbed are susceptible to degradation within the blood with half lives of a few minutes. Furthermore hydrogen bond formation by hydrophilic peptides limits their transport across the blood brain barrier making neuroactive peptides very difficult to deliver via the oral route.
A wide variety of drug delivery vehicles are known. These include, for instance, liposomes, which are composed of a phospholipid bilayer that may act as a carrier for both hydrophilic and hydrophobic drugs.
WO03/033027 teaches the use of cationic dendrimers (for instance, poly(propylenimine) dendrimers with a diaminobutane core) to deliver bioactive molecules such as polynucleotides or polypeptides to a human or animal recipient.
WO2004/026912 describes solubilising polysaccharides which are used to solubilise hydrophobic drugs. The polysaccharides are amphiphilic and are generally selected from any derivatives of the following: chitosans, dextrans, alginic acids, starches, dextran and guar gums. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) and quaternary ammonium cetyl glycol chitosan (GCHQ) are used in the Examples of this patent application as solubilising polysaccharides.
WO2008/017839 describes micellar clusters formed from amphiphilic carbohydrate polymers and their use in formulating hydrophobic drugs. Palmitoyl glycol chitosan is a specifically exemplified amphiphilic carbohydrate polymer. The Patent Application focuses on improved drug delivery to the CNS or cornea. Gastrointestinal delivery of the drugs is briefly mentioned.
Improved oral delivery of poorly soluble drugs is described in WO2004/026941. Amphiphilic polymers, such as poly(ethylenimine) polymers are used.
At a meeting in Innsbruk Austria on 10 Apr. 2008—the INANO Symposium and at a meeting in New York—the 35th Annual CRS Annual Meeting on 14 Jul. 2008 (Lalatsa A, Schatzlein A G, Uchegbu I F, Carbohydrate nanoparticles for peptide delivery to the central nervous system, Abstract 3279), a method of enhancing the bioavailability of Leucine[5]-Enkephalin was disclosed. Leucine[5]-Enkephalin, a hydrophilic peptide was modified by making it more lipophilic. More specifically, a lipid ester pro-drug of Leucine[5]-Enkephalin was formed and added to a composition comprising quaternary ammonium palmitoyl glycol chitosan (GCPQ). The composition was delivered intravenously. The prodrug was converted to Leucine[5]-Enkephalin in vivo. The lipid ester prodrug with GCPQ was shown to result in significantly higher Leucine[5]-Enkephalin brain levels than when Leucine[5]-Enkephalin alone or Leucine[5]-Enkephalin with GCPQ after I.V. administration were used.
Oral delivery of the lipid ester prodrug was not disclosed at this meeting. Indeed, one would not have expected such a composition to be successfully delivered by the oral route, since peptides are notoriously difficult to administer to the body via this route and the lipidised drug, the amphiphilic prodrug, had a molecular weight in excess of 500 Da.
The prior art does not describe how one can successfully deliver hydrophilic drugs to the brain. This invention addresses this short-coming.